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Endocrinology Vol. 140, No. 5 2252-2257
Copyright © 1999 by The Endocrine Society

ARTICLES

Glucose Regulation of Insulin Secretion Independent of the Opening or Closure of Adenosine Triphosphate-Sensitive K+ Channels in ß Cells1

Yoshihiko Sato, Marcello Anello and Jean-Claude Henquin

Unité d’Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, UCL 55.30, B 1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. J. C. Henquin, Unité d’Endocrinologie et Métabolisme, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Two major pathways are implicated in the stimulation of insulin secretion by glucose. The K+-ATP channel-dependent pathway involves closure of these channels, depolarization of the ß-cell membrane, acceleration of Ca2+ influx, and a rise in cytosolic free Ca2+ ([Ca2+]i). The K+-ATP channel-independent pathway potentiates the stimulation of exocytosis by high [Ca2+]i. To determine whether this second pathway is influenced by the configuration of the channel, we compared the effects of glucose on [Ca2+]i and insulin secretion in mouse islets under three conditions. First, in the presence of 20, 25, and 30 mM K+, i.e. without pharmacological action on K+-ATP channels, [Ca2+]i and insulin secretion were already elevated at 3 mM glucose. High glucose (20 mM) caused a transient decrease in [Ca2+]i followed by an ascent to slightly above control levels, and rapidly stimulated insulin secretion. Second, opening of K+-ATP channels with diazoxide did not influence [Ca2+]i and insulin secretion at 3 mM glucose and high K+. However, high glucose now caused a sustained lowering of [Ca2+]i accompanied by a slow increase in secretion that augmented with the K+ concentration. Third, when K+-ATP channels were blocked and ß-cells depolarized by high concentrations of tolbutamide or glibenclamide, [Ca2+]i and insulin secretion were elevated even in low glucose. High glucose transiently lowered [Ca2+]i, which then increased to or slightly above control levels, while insulin secretion was rapidly stimulated. Under all conditions the correlation between [Ca2+]i and insulin secretion was excellent at low and high glucose levels, and high glucose increased release at all [Ca2+]i. The potentiation of Ca2+-induced exocytosis by glucose is thus independent of the closed or open state of K+-ATP channels. It is only when the channels are opened by diazoxide that the increase in release is a strict amplification of the action of Ca2+. When the channels are closed (sulfonylureas) or still closable (high K+ alone), the effect of glucose on secretion also comprises a slight increase in [Ca2+]i and, in the latter case, is not strictly K+-ATP channel independent.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE REGULATION of insulin secretion by glucose involves two major mechanisms. The first identified and best characterized pathway serves to increase the cytoplasmic concentration of Ca2+ ([Ca2+]i) in ß-cells through the following sequence of events (1, 2, 3, 4). Glucose metabolism generates signals, including an increase in the ATP/ADP ratio (5), which close ATP-sensitive K+ (K+-ATP) channels in the plasma membrane. This causes membrane depolarization, opening of voltage-dependent Ca2+ channels, and acceleration of Ca2+ influx. The rise in [Ca2+]i then triggers exocytosis of insulin granules. This pathway is referred to as the K+-ATP channel-dependent pathway because the channel is the key player in the transduction of the glucose effects. A similar pathway underlies the stimulation of insulin secretion by sulfonylureas, which, however, directly block the channel by binding to one of its subunits, the sulfonylurea receptor (6, 7). Conversely, diazoxide inhibits insulin secretion by opening K+-ATP channels and eventually preventing glucose from depolarizing ß-cells and raising [Ca2+]i (1, 2, 3).

The second pathway has been discovered more recently and is known as the K+-ATP channel-independent pathway. It has been identified by using diazoxide to prevent glucose from closing K+-ATP channels and high K+ to restore membrane depolarization, Ca2+ influx, and [Ca2+]i rise in ß-cells (8, 9, 10). Under these conditions glucose did not further increase [Ca2+]i, but potentiated the stimulatory effect of [Ca2+]i on exocytosis (10). The existence of this pathway is now widely accepted (11, 12, 13, 14, 15), and the underlying mechanisms are being progressively unraveled (16).

Another approach to study K+-ATP channel-independent effects of glucose on insulin secretion is to test the effects of the sugar when all K+-ATP channels have been closed by a high concentration of sulfonylurea. Glucose still increases insulin secretion under these conditions (17, 18), and on the basis of measurements of K+ (86Rb) efflux, this effect has been ascribed to a K+-ATP channel-independent depolarizing action of the sugar (18). An alternative explanation, based on measurements of 45Ca efflux from the islets, is that glucose promotes Ca2+ influx through voltage-independent Ca2+ channels (19). It is also known that glucose increases the Ca2+-dependent spike activity in ß-cells depolarized with tolbutamide (20). Collectively, these observations suggest that the effects of glucose in the presence of closed K+-ATP channels might involve a further rise in ß-cell [Ca2+]i and, hence, differ from the K+-ATP channel-independent pathway characterized in the presence of high K+ and diazoxide (8, 10).

In the present study, mouse islets were depolarized either by closing all K+-ATP channels with tolbutamide and glibenclamide or by shifting the equilibrium potential of K+ with a high concentration of extracellular K+, whereas K+-ATP channels were held open with diazoxide or were left untouched and still amenable to blockade by glucose. Three concentrations of K+ were tested to depolarize the membrane as, or slightly more than, does closure of K+-ATP channels. We then measured the influence of glucose on [Ca+2]i and insulin secretion under these three conditions.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study was conducted in accordance with the guidelines of the institutional ethics committee. The experiments were performed with islets isolated by collagenase digestion of the pancreas of fed female NMRI mice (25–30 g), followed by hand-picking (21). After isolation, the islets were cultured for 18–25 h in RPMI 1640 medium (Flow Laboratories, ICN Biomedicals, Inc., Irvine, UK) containing 10 mM glucose, 10% heat-inactivated FCS, 100 IU/ml penicillin, and 100 µg/ml streptomycin.

The medium used for islet isolation was a bicarbonate-buffered solution containing 120 mM NaCl, 4.8 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCl2, and 24 mM NaHCO3. It was gassed with O2-CO2 (94:6) to maintain a pH of 7.4 and was supplemented with 1 mg/ml BSA and 10 mM glucose. The experiments after culture were performed with a similar medium (normal K+ medium) or with one containing 20, 25, or 30 mM KCl (high K+ medium) and only 104.8, 99.8, and 94.8 mM NaCl, respectively. The concentration of glucose was adjusted, and test substances were added as required.

Before measurements of [Ca2+]i, cultured islets were first preincubated for 120 min in normal K+ medium containing 5 mM glucose and 2 µM fura PE3 acetoxymethylester (Mobitec, Gottingen, Germany). The islets were then transferred into a temperature-controlled perifusion chamber (Intracell, Royston, Herts, UK) with a bottom made of a coverslip and mounted on the stage of an inverted microscope. [Ca2+]i was then measured as previously described (10, 22). The same protocol was tested with three or four islets at a time and was repeated with islets from four to seven different preparations.

Before measurements of insulin secretion, cultured islets were first preincubated for 90 min in normal K+ medium containing 5 mM glucose. Batches of 20 islets were then transferred into perifusion chambers and perifused at a flow rate of 1.2 ml/min (23). Effluent fractions were collected at 1- or 2-min intervals, and their insulin content was measured by a double antibody RIA with rat insulin as the standard (Novo Research Institute, Bagsvaerd, Denmark). The same protocol was tested with only one batch of islets from each culture, but was repeated with islets from different preparations.

Results are presented as the mean ± SEM. The statistical significance of differences between means was assessed by ANOVA followed by Newman-Keuls test or Student’s t test when only two groups were compared.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiments in the presence of high K+without and with diazoxide
When mouse islets were perifused with a normal K+ medium containing 3 mM glucose (not shown), [Ca2+]i was between 70–90 nM in 3 mM glucose (8, 22) and between 200–240 nM during stimulation with maximally effective glucose concentrations (24) (Sato, Y., and J.-C. Henquin, unpublished observations). In the presence of high K+ and 3 mM glucose, [Ca2+]i was elevated to 208 ± 8 nM (K+20), 240 ± 10 nM (K+25), and 293 ± 8 nM (K+30). This elevated [Ca2+]i slightly increased with time when the glucose concentration remained at 3 mM (Fig. 1Go). Raising the glucose concentration to 20 mM caused an initial, transient, decrease in [Ca2+]i followed by a rise above control values at K+20 and K+25 and a return to control values at K+30 (Fig. 1Go, left panels). Figure 2Go (upper panel) compares the steady state changes in [Ca2+]i produced by 20 mM glucose to the spontaneous rise occurring at 3 mM glucose. When the glucose concentration was eventually lowered to 3 mM at 26 min, [Ca2+]i decreased, which attests to the existence of a sustained stimulatory effect of high glucose (Fig. 1Go, left panels).



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  		Figure 1. Effects of glucose on [Ca2+]i in mouse islets depolarized with high K+. The perifusion medium contained 20, 25, or 30 mM K+ without or with 250 µM diazoxide (Dz) as indicated. Control experiments were performed in the presence of 3 mM glucose throughout. In test experiments, the concentration of glucose was increased from 3 to 20 mM between 6–26 min. Values are the mean ± SEM for 16–28 islets from 4–6 separate experiments.

 


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  		Figure 2. Quantification of the changes in [Ca2+]i brought about by glucose in mouse islets depolarized with high K+ or sulfonylureas. The values were calculated from the experiments shown in Figs. 1Go and 4Go. For each islet, the average [Ca2+]i between 4–6 min was subtracted from that between 14–16 min. The open bars reflect the small rise in [Ca2+]i occurring under control conditions. The real effect of glucose corresponds therefore to the difference between open and hatched bars, and its statistical significance (P < 0.001 or less) is indicated by an asterisk. Values are the mean ± SEM for 16–31 islets from 4–7 separate experiments.

 
When the medium containing 3 mM glucose was supplemented with 250 µM diazoxide, [Ca2+]i averaged 196 ± 7 nM (K+20), 250 ± 9 (K+25), and 287 ± 7 nM (K+30). These values are not significantly different from those measured in the absence of diazoxide. In contrast, raising the concentration of glucose to 20 mM caused a rapid decrease in [Ca2+]i that persisted (P < 0.001) until return to a low glucose medium (Fig. 1Go, right panels). The difference between [Ca2+]i at 20 mM glucose and that of controls kept at 3 mM glucose was significant at the three K+ concentrations (Fig. 2Go). In addition, at 20 mM glucose and 20, 25, or 30 mM K+, [Ca2+]i was lower (P < 0.001) in the presence than absence of diazoxide.

When mouse islets are perifused with a normal K+ medium containing 3 mM glucose (not shown), the basal rate of insulin secretion is around 10 pg/islet·min. In the experiments shown in Fig. 3Go, insulin secretion was stimulated by high K+. The initial peak of K+-induced secretion (10) is not visible because it occurred before collection of the samples. The period 15–25 min corresponds to the sustained effect of high K+. This effect was clearly concentration dependent: 47 ± 7 pg/islet·min (K+20), 84 ± 15 pg/islet·min (K+25), and 94 ± 11 pg/islet·min (K+30). Raising the glucose concentration to 20 mM in the presence of high K+ markedly and reversibly stimulated insulin secretion (Fig. 3Go). The steady state rate of secretion slightly increased with the concentration of K+: 205 ± 33 pg/islet·min (K+20), 249 ± 37 pg/islet·min (K+25), and 295 ± 31 pg/islet·min (K+30).



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  		Figure 3. Effects of glucose on insulin secretion from mouse islets depolarized with high K+. The perifusion medium contained 20, 25, or 30 mM K+ without or with 250 µM diazoxide (Dz) as indicated. The concentration of glucose was increased from 3 to 20 mM between 25–55 min. Values are the mean ± SEM for seven or eight separate and paired (± diazoxide) experiments.

 
When the medium containing 3 mM glucose was supplemented with 250 µM diazoxide, insulin secretion was also stimulated by high K+, and this stimulation was not different from that in the absence of diazoxide (Fig. 3Go). The presence of diazoxide, however, made the response to high glucose very dependent on the concentration of K+. Upon stimulation with 20 mM glucose, insulin secretion increased to 130% (K+20), 195% (K+25), and 275% (K30%) of the control values in 3 mM glucose. In K+30, the steady state response was close to that observed in the absence of diazoxide, but the changes were slower.

Experiments in the presence of sulfonylureas
When the normal K+ medium containing 3 mM glucose also contained a high concentration of sulfonylurea to block all K+-ATP channels, islet [Ca2+]i was increased to 234 ± 8 nM (tolbutamide) and 251 ± 11 nM (glibenclamide). This high [Ca2+]i slightly increased with time when the glucose concentration remained at 3 mM (Fig. 4Go). Raising the glucose concentration to 20 mM caused a rapid transient decrease in [Ca2+]i followed by a return to (glibenclamide) or slightly above (tolbutamide) control values (Figs. 2Go and 4Go). The final lowering of glucose to 3 mM was accompanied by a small, transient increase in [Ca2+]i (Fig. 4Go). The rate of insulin secretion at 3 mM glucose was increased by tolbutamide (68 ± 19 pg/islet·min) and glibenclamide (77 ± 15 pg/islet·min), and the rise in the glucose concentration to 20 mM produced a 3- to 4-fold potentiation (Fig. 5Go).



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  		Figure 4. Effects of glucose on [Ca2+]i in mouse islets depolarized with 500 µM tolbutamide (Tolb) or 2 µM glibenclamide (Glib) as indicated. Control experiments were performed in the presence of 3 mM glucose throughout. In test experiments, the concentration of glucose was increased from 3 to 20 mM between 6–26 min. Values are the mean ± SEM for 21–31 islets from 5–7 separate experiments.

 


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  		Figure 5. Effects of glucose on insulin secretion from mouse islets depolarized with 500 µM tolbutamide (Tolb) or 2 µM glibenclamide (Glib) as indicated. The concentration of glucose was increased from 3 to 20 mM between 25–55 min. Values are the mean ± SEM for five separate experiments.

 
Correlations between [Ca2+]i and insulin secretion
Figure 6Go shows the relationships between islet [Ca2+]i and insulin secretion when the islets were depolarized by high K+ alone, by high K+ in the presence of diazoxide, or by sulfonylureas. The correlation is excellent at both 3 and 20 mM glucose. Importantly, the secretory response to a given [Ca2+]i is larger in high than in low glucose, which demonstrates the amplification of the action of Ca2+ by glucose.



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  		Figure 6. Correlations between [Ca2+]i and insulin secretion in mouse islets depolarized with high K+ or sulfonylureas. The values are taken from the experiments shown in Figs. 1Go, 3Go, 4Go, and 5Go. The symbols correspond to the following conditions: high K+ without diazoxide ({circ}), high K+ with diazoxide (•), and tolbutamide or glibenclamide ({blacktriangleup}). The values correspond to averages of [Ca2+]i between 4–6 and 14–16 min and averages of insulin secretion between 15–25 and 35–45 min in 3 and 20 mM glucose, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A rise in ß-cell [Ca2+]i is essential for the stimulation of insulin secretion by most secretagogues, including glucose. The present study shows that there exists a tight correlation between insulin secretion and [Ca2+]i in intact mouse islets. Because of the limitations of fluorescent dye techniques for [Ca2+]i measurements in multicellular organs, such as the islet of Langerhans, the reported values should be regarded as mean estimates. These, however, adequately reflect [Ca2+]i that is critical for secretion. Otherwise, no quantitative correlation could be observed between both parameters, nor would oscillations of insulin secretion occur synchronously with [Ca2+]i oscillations recorded by this method (21, 25, 26, 27, 28). The same relationship between insulin secretion and [Ca2+]i characterized three sets of experimental conditions: high K+ alone, high K+ with diazoxide, and sulfonylureas. A major conclusion is that the action of Ca2+ on secretion is independent of the closed or open state of K+-ATP channels and thus of the mechanism by which the ß-cell membrane is depolarized.

The results obtained with tolbutamide and glibenclamide did not deviate from the [Ca2+]i/secretion relationship established with high K+. This reinforces the conclusions of our previous reports that, contrary to a suggestion by others (29), sulfonylureas do not affect insulin secretion by a mechanism other than the change in [Ca2+]i in intact islets (30, 31). Similarly, the presence of diazoxide did not influence insulin secretion in a way that could not be accounted for by a difference in [Ca2+]i. In other words, neither sulfonylureas nor diazoxide altered the effect of Ca2+ on the secretory machinery. In contrast, the relationship between insulin secretion and [Ca2+]i was very different in low and high glucose. Glucose increased the efficacy of Ca2+ on insulin secretion, which is the characteristic of the K+-ATP channel-independent pathway of regulation of insulin secretion (8, 10, 32). This effect of glucose requires metabolism of the sugar and appears to depend on changes in adenine and guanine nucleotides, whereas the protein kinase A, protein kinase C, nitric oxide-protein kinase G, long chain acyl coenzyme A, and phospholipase A2-arachidonic acid pathways seem to play no or only a minor role (5, 10, 11, 12, 16, 33, 34).

That glucose increases the efficacy of cytosolic Ca2+ on insulin secretion was here demonstrated under three different conditions: high K+ with diazoxide, high K+ alone and high sulfonylureas. However, the increase in insulin secretion brought about by glucose involves more than one mechanism in two of these three conditions.

When islets are perifused with a medium containing 30 mM K+ and diazoxide, the ß-cell membrane is depolarized, [Ca2+]i is high, and glucose cannot close K+-ATP channels. It has no effect on the membrane potential, but causes a rapid fall in [Ca2+]i followed by a climb to values remaining lower than those in controls maintained in a low glucose medium (8). This observation was entirely confirmed by the present study, which further showed that the steady state decrease in [Ca2+]i was more marked in 20–25 mM K+ than in 30 mM K+. The underlying mechanisms were not explored here, but measurements of 45Ca efflux from islets loaded with the tracer indicate that Ca2+ sequestration in intracellular organelles at least partially explains these changes in [Ca2+]i (8). It is undisputable that under these conditions of ß-cell depolarization with open K+-ATP channels, glucose increases insulin secretion while decreasing [Ca2+]i. As this effect on secretion requires Ca2+, it is thus entirely attributable to an increase in Ca2+ efficacy on exocytosis.

When islets were depolarized by 30 mM K+ in the absence of diazoxide and glucose, subsequent application of 20 mM glucose caused a further, slight depolarization and increased the noise of the membrane potential (8). In 20 and 25 mM K+, raising the glucose concentration from 3 to 20 mM also caused a 5- to 7-mV depolarization and induced electrical activity (Ca2+ spikes) (Henquin, J.-C., unpublished data). As these effects are abrogated by diazoxide, it is clear that glucose can promote a K+-ATP channel-dependent stimulation of Ca2+ influx in ß-cells depolarized by 20–30 mM K+. This effect partially masks the initial fall in [Ca2+]i and is followed by a rise above or to control levels, which makes a substantial difference with the steady state decrease occurring in the presence of diazoxide. This dual action of glucose may also explain distinct kinetics in the changes; in 30 mM K+, the increase in secretion induced by 20 mM glucose was faster in the absence than in the presence of diazoxide, although similar steady state effects were eventually reached. Variations in [Ca2+]i appear to exert a more rapid control of insulin secretion than do variations in Ca2+ efficacy. The increase in insulin secretion that glucose produces in islets depolarized by high K+ alone (when K+-ATP channels are still blockable) thus includes two components: a rise in [Ca2+]i and an amplification of the action of Ca2+. It is not a pure K+-ATP channel-independent phenomenon.

When islets were depolarized by closure of K+-ATP channels with a sulfonylurea, raising the concentration of glucose from 3 to 20 mM caused a transient decrease in[Ca2+]i, as previously reported (35, 36). This decrease in [Ca2+]i in islet cells was accompanied by a short-lived inhibition of insulin secretion (35) that was also observed with intact islets submitted to a similar protocol (17). We only occasionally observed such an inhibition, probably because the islets were not perfectly synchronized in the chamber of a perifusion system with too long a dead space to permit resolution of such a short-lived event. The transient fall in [Ca2+]i produced by glucose in the presence of a sulfonylurea has been attributed to Ca2+ sequestration (35, 36). A transient repolarization of the ß-cell membrane has also been reported (37), but our previous experiments showed that the membrane remains depolarized, and the spike frequency actually increases under these conditions (20). This increase in spike activity may explain why [Ca2+]i then reaches levels similar to or even slightly higher than those in controls despite the stimulated sequestration. As the concentrations of 500 µM tolbutamide and 2 µM glibenclamide largely exceed those required to block K+-ATP channels completely (1, 7, 38), the effects of glucose can be considered to be K+-ATP channel independent. They might occur at the level of voltage-dependent Ca2+ channels (39). The potentiation of insulin secretion that glucose causes after pharmacological blockade of K+-ATP channels may thus be considered to be a K+-ATP channel-independent phenomenon, but appears to involve a slight increase in [Ca2+]i in addition to a large amplification of the action of Ca2+.

In conclusion, the control of insulin secretion that glucose exerts by modulating the efficacy of Ca2+ on exocytosis is independent of the closed or open state of K+-ATP channels. Evidently, under physiological conditions, when glucose itself regulates the ß-cell membrane potential, the channels are largely closed. From a practical standpoint it is also clear that the experimental conditions used to study K+-ATP channel-independent effects of glucose are not interchangeable. Actions of glucose on other targets, e.g. Ca2+ channels, may complicate the picture, and a correct interpretation of the results is not possible without concomitant measurements of ß-cell [Ca2+]i.


   Acknowledgments
 
We thank F. Knockaert and L. Cnops for technical assistance, and S. Roiseux for editorial help.


   Footnotes
 
1 This work was supported by Grant 3.4552.98 from the Fonds de la Recherche Scientifique Médicale (Brussels, Belgium), Grant 95/00–188 from the General Direction of Scientific Research of the French Community of Belgium, and the Interuniversity Poles of Attraction Program (P4/21)-Belgian State, Prime Minister’s Office, Federal Office for Scientific, Technical, and Cultural Affairs. Back

Received November 2, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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